Pravastatin therapy is associated with reduction in coronary allograft vasculopathy in pediatric heart transplantation.

BACKGROUND: Hydroxymethylglutaryl CoA reductase inhibitors (statins) have been demonstrated to reduce the risk of developing coronary allograft vasculopathy (CAV) following heart transplantation in adults and are used routinely in many centers. CAV and lipid abnormalities have been reported to be less prevalent in pediatric heart transplant recipients. It is not known whether statins reduce the risk of CAV in this population METHODS: A retrospective review was performed to analyze the risk factors for developing CAV following pediatric heart transplantation with particular attention to the impact of pravastatin therapy. The study population was comprised of 129 pediatric patients who underwent 142 heart transplants at our institution from 1988 to 2003. The outcome variable was freedom from CAV, CAV being determined by coronary angiography or autopsy. RESULTS: CAV was identified in 25 recipients at a median of 3.7 years after transplantation. There were 331 patient-years of pravastatin therapy. Pravastatin therapy resulted in a reduction in total cholesterol levels, 162 +/- 29 to 137 +/- 20 mg/dl, p = 0.01. In multivariate analysis the use of pravastatin was associated with a lower incidence of CAV (p = 0.03), whereas an increased frequency of late rejection (p = 0.003) and earlier year of transplantation (p = 0.04) were associated with increased risk of CAV. CONCLUSIONS: The routine use of pravastatin was associated with a lower risk following pediatric heart transplantation. Further studies into the relationship between lipid abnormalities, inflammation and rejection, and the development of CAV in children are warranted.     

Whose Line Is It Anyway?: Dismantling the Foundations of Rape Culture

Archives of Sexual Behavior -     

Plain Language for Patient Education

Low health literacy continues to be a barrier in patient education. One solution to low health literacy is creating or providing patient education materials written in plain language. Plain language follows guidelines created for federal agencies to ensure that documents are written in clear and accessible language for all audiences. Health care professionals and librarians can locate or recommend plain language health information from many reputable consumer health websites.     

Stakeholder-Generated Implementation Strategies to Promote Evidence-Based ADHD Treatment in Community Mental Health

Community implementation of evidence-based practices (EBPs) for Attention Deficit/Hyperactivity Disorder (ADHD) is greatly lacking. A recent randomized community-based trial of an EBP for ADHD (Supporting Teens’ Autonomy Daily; STAND) demonstrated suboptimal implementation and effectiveness outcomes. In the present study, we conducted an Innovation Tournament (IT) with agency staff stakeholders (N?=?26) to identify barriers to successful implementation of STAND and implementation strategies for a revised service delivery model. We conducted member-checking of agency staff-generated ideas with parents (N?=?226) and subsequent querying of additional parent (N?=?226) and youth-generated (N?=?205) strategies to improve care. Go-Zone plots were utilized to identify strategies with the highest feasibility and importance. Practical barriers (i.e., transportation, scheduling difficulties) and parent/youth engagement were the most commonly cited obstacles to successful implementation of STAND in community contexts. Eighteen “winning” implementation strategies were identified that survived member checking. These were classified as train and educate stakeholders (n?=?5; e.g., train agency supervisors to deliver supervision, digitize treatment materials and trainings), engage consumers (n?=?9; e.g., begin treatment with rapport building sessions, increase psychoeducation), provide interactive assistance (n?=?2; e.g., add group supervision, increase roleplay in supervision), and use of evaluative/iterative strategies (n?=?2; e.g., perform fidelity checks, supervisor review of session recordings). Parents and youth desired longer duration of treatment and increased focus on maintenance. Strategies will be developed and tested as part of a pilot effectiveness trial designed to refine STAND’s service delivery model.

Trial Registration NCT02694939 www.clinicaltrials.gov

     

Rare recombination events generate sequence diversity among balancer chromosomes in Drosophila melanogaster

Multiply inverted balancer chromosomes that suppress exchange with their homologs are an essential part of the Drosophila melanogaster genetic toolkit. Despite their widespread use, the organization of balancer chromosomes has not been characterized at the molecular level, and the degree of sequence variation among copies of balancer chromosomes is unknown. To map inversion breakpoints and study potential diversity in descendants of a structurally identical balancer chromosome, we sequenced a panel of laboratory stocks containing the most widely used X chromosome balancer, First Multiple 7 (FM7). We mapped the locations of FM7 breakpoints to precise euchromatic coordinates and identified the flanking sequence of breakpoints in heterochromatic regions. Analysis of SNP variation revealed megabase-scale blocks of sequence divergence among currently used FM7 stocks. We present evidence that this divergence arose through rare double-crossover events that replaced a female-sterile allele of the singed gene (sn^X2) on FM7c with a sequence from balanced chromosomes. We propose that although double-crossover events are rare in individual crosses, many FM7c chromosomes in the Bloomington Drosophila Stock Center have lost sn^X2 by this mechanism on a historical timescale. Finally, we characterize the original allele of the Bar gene (B¹) that is carried on FM7, and validate the hypothesis that the origin and subsequent reversion of the B¹ duplication are mediated by unequal exchange. Our results reject a simple nonrecombining, clonal mode for the laboratory evolution of balancer chromosomes and have implications for how balancer chromosomes should be used in the design and interpretation of genetic experiments in Drosophila.Balancer chromosomes are genetically engineered chromosomes that suppress crossing over with their homologs and are used for many purposes in genetics, including construction of complex genotypes, maintenance of stocks, and estimation of mutation rates. Balancers typically carry multiple inversions that suppress genetic exchange or result in the formation of abnormal meiotic products if crossing over does occur (Fig. 1A); for example, single crossovers inside the inverted segment create acentric or dicentric chromosomes that will fail to segregate properly during meiosis or large deletions or duplications that will likely result in inviable gametes (1, 2). Balancers also often carry recessive lethal or sterile mutations to prevent their propagation as homozygotes as well as dominant markers for easy identification. First developed for use in Drosophila melanogaster, balancer chromosomes remain some of the most powerful tools for genetic analysis in this species (3).Open in a separate windowFig. 1.Consequences of a single or double crossover between a WT X chromosome and an X chromosome carrying a single inversion, In(1)dl-49. Euchromatin is shown in blue, heterochromatin is shown in gray, and centromeres are depicted as circles. Thin white lines mark locations of inversion breakpoints, and yellow crosses/thin lines mark locations of crossover events. (A) A single crossover event within the inverted segment results in the formation of chromosomes with deletions and zero (acentric) centromeres or duplications and two (dicentric) centromeres, neither of which will segregate properly during meiosis. (B) A double crossover within an inverted segment results in intact chromosomes with one centromere that will segregate properly during meiosis.Despite their widespread use, very little is known about the organization of Drosophila balancer chromosomes at the molecular level. Since their original syntheses decades ago, balancers have undergone many manipulations, including the addition or removal of genetic markers. Moreover, rare recombination events can cause spontaneous loss of deleterious alleles on chromosomes kept over balancers in stock, as well as loss of marker alleles on balancer chromosomes themselves (3). Likewise, recent evidence has shown that sequence variants can be exchanged between balancer chromosomes and their wild type (WT) homologs via gene conversion during stock construction or maintenance (4, 5). Thus, substantial variation may exist among structurally identical balancer chromosomes owing to various types of sequence exchange.To gain insight into the structure and evolution of balancer chromosomes, we have undertaken a genomic analysis of the most commonly used X chromosome balancer in D. melanogaster, First Multiple 7 (FM7). We have focused on FM7 because this X chromosome balancer series lacks lethal mutations and thus can be easily sequenced in a hemizygous or homozygous state. In addition, the FM7 chromosome has been shown to pair normally along most of its axis with a standard X chromosome, providing a structural basis for possible exchange events (6). Moreover, although details of how early balancers in D. melanogaster were created are not fully recorded, the synthesis and cytology of the FM7 series is reasonably well documented (3).The earliest chromosome in the FM7 series, FM7a, was constructed using two progenitor X chromosome balancers, FM1 and FM6, to create a chromosome carrying three inversions—In(1)sc⁸, In(1)dl-49, and In(1)FM6—relative to the WT configuration (7, 8) (Fig. 2A). Subsequently, a female-sterile allele of singed (sn^X2) was introduced onto FM7a to create FM7c, which prevents the loss of balanced chromosomes carrying recessive lethal or female-sterile mutations (9). More recently, versions of FM7a and FM7c have been generated that carry transgene insertions that allow the determination of balancer genotypes in embryonic or pupal stages (10–14).Open in a separate windowFig. 2.Structure of the FM7 balancer chromosome. Euchromatin is shown in blue, and heterochromatin is shown in gray. (A) Schematic view of the organization of WT and FM7 X chromosomes. FM7 contains three inversions—In(1)sc⁸, In(1)dl-49, and In(1)FM6—relative to WT. The six breakpoint junctions for the three inversions are numbered 1–6 and are shown in detail in B. (B) Location and organization of inversion breakpoints in FM7. Each inversion has two breakpoints that can be represented as A/B and C/D in the standard WT arrangement and as A/C and B/D in the inverted FM7 arrangement, where A, B, C, and D represent the sequences on either side of the breakpoints. Locations of euchromatic breakpoints are on Release 5 genome coordinates, and the identity of the best BLAST match in FlyBase is shown for heterochromatic sequences. Primers used for PCR amplification are shown above each breakpoint; details are provided in Methods and Datasets S2 and S3. Forward and reverse primers are named with respect to the orientation of the assembled breakpoint contigs, not the orientation of the WT or FM7 X chromosome.To identify the inversion breakpoints in FM7 balancers and to study patterns of sequence variation that may have arisen since the origin of the FM7 series, we sequenced genomes of eight D. melanogaster stocks carrying the FM7 chromosome (four FM7a and four FM7c). We discovered several megabase-scale regions in which FM7c chromosomes differ from one another, which presumably arose via double-crossover (DCO) events from balanced chromosomes (Fig. 1B). These DCOs eliminate the female-sterile sn^X2 allele in the centrally located In(1)dl-49 inversion and are expected to confer a fitness advantage to sn⁺ chromosomes, either by allowing propagation of sn⁺ FM7 as homozygotes in females or by sn⁺ FM7 males outcompeting sn^X2 FM7 males in culture. We found that loss of the sn^X2 allele is common in FM7c chromosomes by screening other FM7c-carrying stocks at the Bloomington Drosophila Stock Center. We also identified the breakpoints of the B¹ duplication carried on FM7, and found direct molecular evidence for the role of unequal exchange in the origin and reversion of the B¹ allele (15–19). Our results provide clear evidence that the common assumption that balancers are fully nonrecombining chromosomes is incorrect on a historical timescale, and that substantial sequence variation exists among balancer chromosomes in circulation today.     

Early Childhood Gut Microbiomes Show Strong Geographic Differences Among Subjects at High Risk for Type 1 Diabetes

OBJECTIVE

Gut microbiome dysbiosis is associated with numerous diseases, including type 1 diabetes. This pilot study determines how geographical location affects the microbiome of infants at high risk for type 1 diabetes in a population of homogenous HLA class II genotypes.

RESEARCH DESIGN AND METHODS

High-throughput 16S rRNA sequencing was performed on stool samples collected from 90 high-risk, nonautoimmune infants participating in The Environmental Determinants of Diabetes in the Young (TEDDY) study in the U.S., Germany, Sweden, and Finland.

RESULTS

Study site–specific patterns of gut colonization share characteristics across continents. Finland and Colorado have a significantly lower bacterial diversity, while Sweden and Washington state are dominated by Bifidobacterium in early life. Bacterial community diversity over time is significantly different by geographical location.

CONCLUSIONS

The microbiome of high-risk infants is associated with geographical location. Future studies aiming to identify the microbiome disease phenotype need to carefully consider the geographical origin of subjects.